Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed

The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations

The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings

The Origin, Early Evolution and Predictability of Solar Eruptions

Coronal mass ejections (CMEs) were discovered in the early 1970s when space-borne coronagraphs revealed that eruptions of plasma are ejected from the Sun. Today, it is known that the Sun produces eruptive flares, filament eruptions, coronal mass ejections and failed eruptions; all thought to be due to a release of energy stored in the coronal magnetic field during its drastic reconfiguration. This review discusses the observations and physical mechanisms behind this eruptive activity, with a view to making an assessment of the current capability of forecasting these events for space weather risk and impact mitigation. Whilst a wealth of observations exist, and detailed models have been developed, there still exists a need to draw these approaches together. In particular more realistic models are encouraged in order to asses the full range of complexity of the solar atmosphere and the criteria for which an eruption is formed. From the observational side, a more detailed understanding of the role of photospheric flows and reconnection is needed in order to identify the evolutionary path that ultimately means a magnetic structure will erupt

A systematic literature review of disclosure practices and reported outcomes for medically actionable genomic secondary findings

PURPOSE: Secondary findings (SFs) are present in 1-4% of individuals undergoing genome/exome sequencing. A review of how SFs are disclosed and what outcomes result from their receipt is urgent and timely. METHODS: We conducted a systematic literature review of SF disclosure practices and outcomes after receipt including cascade testing, family and provider communication, and health-care actions. Of the 1,184 nonduplicate records screened we summarize findings from 27 included research articles describing SF disclosure practices, outcomes after receipt, or both. RESULTS: The included articles reported 709 unique SF index recipients/families. Referrals and/or recommendations were provided 647 SF recipients and outcome data were available for 236. At least one recommended evaluation was reported for 146 SF recipients; 16 reports of treatment or prophylactic surgery were identified. We found substantial variations in how the constructs of interest were defined and described. CONCLUSION: Variation in how SF disclosure and outcomes were described limited our ability to compare findings. We conclude the literature provided limited insight into how the American College of Medical Genetics and Genomics (ACMG) guidelines have been translated into precision health outcomes for SF recipients. Robust studies of SF recipients are needed and should be prioritized for future research